T cells arise from stem cells in the bone marrow (Fig 5-1). After pre-T cells leave the bone marrow, they undergo further maturation in the thymus gland. Thus, T cells are sometimes referred to as thymus-dependent lymphocytes.

During the final stage of T-cell development, the cells migrate from the thymus to the blood and lymphatic system. The preponderance of circulating lymphocytes are T cells, and they recirculate constantly from the bloodstream to the lymphatics. From the bloodstream they enter and patrol the tissues.

Mature T cells are located in the peripheral lymphoid tissues, particularly in the paracortical region of the lymph nodes (Fig 5-2) and in the periarteriolar portions of the white pulp of the spleen.

There are two basic subsets of T cells, those that express surface CD4 antigens and those that express CD8 antigens. (Note: CD stands for cluster designation.)

CD4+ T cells are helper cells that secrete soluble factors (cytokines) that influence virtually all of the cells of the immune system, including other T cells, B cells, macrophages, and NK cells. There are two subsets of these cells, Th1 and Th2 cells, to be discussed later.

CD8+ T cells are either cytotoxic or suppressor cells. Suppressor cells inhibit the immune response to a specific antigen or immune cell; they do not suppress responses to other antigenic determinants. Thus they can serve in a regulatory capacity over the immune system. Here are your MPs!

Figure 5-3 provides an example of how helper and suppressor T cells influence a B cell that has bound specific antigen to its receptors. The T-helper cell promotes proliferation and differentiation, whereas the suppressor cell has blocked proliferation.

Fig 5-1 Immune response.

Fig 5-2 Lymph node.

Fig 5-3 T-cell regulatory functions.

Cytotoxic T lymphocytes (CTLs) are able to kill antigen-bearing cells such as tumor cells or virus-infected cells. These CD8+ T cells kill target cells by direct contact, that is, killing only takes place when the CTL and its target cell come together so that their cell membranes are in direct contact (Fig 5-4).

The exact mechanism of killing is not known, but it may involve the release of perforin, a Ca⁺⁺-dependent protein, from secretory granules in CTLs. Perforin is similar to C9 of the complement system in that it can insert itself into the membrane of a target cell and produce cell lysis. CTLs also release serine hydrolases. The role of these proteolytic hydrolases is unclear, but specific hydrolase inhibitors block the cyotoxicity of CTLs.

CTLs can also elaborate tumor necrosis factor-beta (TNF-β), which has the ability to kill certain cells by a process known as apoptosis (programmed cell death), in which there is a very rapid fragmentation of the target cell nucleus.

Fig 5-4 Cytotoxic T lymphocyte.

CD4 is present on 60% of peripheral T cells, whereas CD8 is present on 30%. The ratio of CD4+ to CD8+ lymphocytes in the blood of healthy individuals is approximately 2 to 1.

1. Sensitized T cells reach the site of antigen deposition.
2. Upon contacting the antigen, they release cytokines (see page 88).
3. Among other things, cytokines have the ability to make nonsensitized T cells behave as though they are sensitized, that is, they too will release cytokines and do other things sensitized lymphocytes can do (even though they are not precommitted to respond to the same antigen). Interleukin-1 and interleukin-2 facilitate this process (Fig 5-5).
4. T-cell cytokines also recruit other cells, notably macrophages and PMNs.

Fig 5-6 Plasma cells (arrows) in an inflammatory cell infiltrate.

B cells are present in blood (10% to 20% of the lymphocytes in circulating blood), lymphoid tissue, and bone marrow. In immune reactions, they give rise to antibody-producing plasma cells (Fig 5-6).

B-cell precursors migrate from the embryonic yolk sac to the fetal liver and later to the bone marrow, where they multiply and diversify into numerous clones (see Fig 5-1). Immature B cells express surface monomeric lgM; surface IgD appears when the B cell is mature. Differentiated B cells accumulate in or near the germinal centers in the follicles of extrathymic lymphoid tissues, that is, lymph nodes (see Fig 5-2) and spleen.

B-cell activation generally requires two signals: the binding of antigen to the B cell’s receptors, and stimulation of the B cell by T-cell cytokines. Any given antigen usually activates both T cells and B cells. In many cases, T cells and B cells are functional partners in producing full immunologic reactivity. They do not work alone.

T-helper cells bind to antigen on the surface of a B cell that has already bound itself to the antigen. The helper cell then promotes activation and maturation of the B cell.

Antigens that can evoke an antibody response are referred to as T-independent antigens. These are typically polymeric and large in size with repeating antigenic sequences. At times, these antigens can activate a large number of B cells nonspecifically, a phenomenon referred to as polyclonal B-cell activation. A number of infectious agents are capable of causing this form of activation (eg, Epstein-Barr virus, LPS, and Borrelia burgdorferi [Lyme disease]).

Fig 5-7 NK cell killing.

NK cells do not recognize antigen, so they require neither antigen processing nor presentation of antigen for activation. Therefore they can be mobilized quickly, days before a more specific T-cell response can be generated. They can kill various target cells directly, and they are also able to mediate antibody-dependent cellular cytotoxicity. This is because these cells have Fc receptors and can bind to cell-bound antibody via the Fc portion of the antibody (ADCC) (Fig 5-7).

Granules within NK cells (as well as the cytoplasm of CTLs) contain a pore-forming protein, called perforin. Degranulation results in the secretion of perforin into the extracellular space between the NK cell and the target cell. Perforin is then inserted into the plasma membrane of the target cell and produces pores with internal diameters of up to 20 nm in the membrane. This destroys the target cell s permeability barrier. (This is similar to the MAC of complement, discussed earlier. In fact, antibodies against perforin cross react with the MAC of complement.)

Recent experiments suggest that perforin is employed in situations in which there are high local concentrations of interleukin-2, such as cancer and acute viral infections.

NK cells respond rapidly to cytokines such as IL-2 and interferon to generate both a proliferative and cytologic response.

Because NK cells can lyse target cells without any apparent previous sensitization and without involvement of major histocompatibility complex (MHC) antigens, they play a key role in immune surveillance.

You may come across the term lymphokine-activated killer (LAK) cells. These are peripheral blood lymphocytes (PBLs) that have been incubated in culture with high levels of IL-2. They are similar to NK cells but the range of cells they can kill is much greater. Most of these LAK cells are derived from NK cells but some are from CTLs. When injected into the cancer patient from which the PBLs were withdrawn, marked regression of tumors has been reported. However, adverse side effects have limited this form of cancer therapy.